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Browsing by Subject "Calreticulin"
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Item Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins(eLife Sciences, 2023-03-21) Li, Kexin; Huo, Qingji; Dimmitt, Nathan H.; Qu, Guofan; Bao, Junjie; Pandya, Pankita H.; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Kacena, Melissa A.; Pollok, Karen E.; Lin, Chien-Chi; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyOsteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.Item Suppression of osteosarcoma progression by engineered lymphocyte-derived proteomes(Elsevier, 2022-08-28) Li, Kexin; Sun, Xun; Li, Hudie; Ma, Hailan; Zhou, Meng; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Pandya, Pankita H.; Saadatzadeh, M. Reza; Kacena, Melissa A.; Pollok, Karen E.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyCancer cells tend to develop resistance to chemotherapy and enhance aggressiveness. A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents. Based on this strategy, induced tumor-suppressing cells (iTSCs) have been generated from tumor cells and mesenchymal stem cells. Here, we examined the possibility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the progression of osteosarcoma (OS). While lymphocyte-derived CM did not present anti-tumor capabilities, the activation of PKA converted them into iTSCs. Inhibiting PKA conversely generated tumor-promotive secretomes. In a mouse model, PKA-activated CM suppressed tumor-induced bone destruction. Proteomics analysis revealed that moesin (MSN) and calreticulin (Calr), which are highly expressed intracellular proteins in many cancers, were enriched in PKA-activated CM, and they acted as extracellular tumor suppressors through CD44, CD47, and CD91. The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr. We envision that identifying these tumor suppressors and predicting their binding partners such as CD44, which is an FDA-approved oncogenic target to be inhibited, may contribute to developing targeted protein therapy.